학술논문
Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis.
Document Type
Article
Author
Isermann, Berend; Vinnikov, Ilya A.; Madhusudhan, Thati; Herzog, Stefanie; Kashif, Muhammed; Blautzik, Janusch; Corat, Marcus A. F.; Zeier, Martin; Blessing, Erwin; Oh, Jun; Gerlitz, Bruce; Berg, David T.; Grinnell, Brian W.; Chavakis, Triantafyllos; Esmon, Charles T.; Weiler, Hartmut; Bierhaus, Angelika; Nawroth, Peter P.
Source
Subject
*PROTEIN C
*DIABETIC nephropathies
*VASCULAR endothelial growth factors
*HYPERGLYCEMIA
*APOPTOSIS
*GLOMERULAR filtration rate
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Language
ISSN
1078-8956
Abstract
Data providing direct evidence for a causative link between endothelial dysfunction, microvascular disease and diabetic end-organ damage are scarce. Here we show that activated protein C (APC) formation, which is regulated by endothelial thrombomodulin, is reduced in diabetic mice and causally linked to nephropathy. Thrombomodulin-dependent APC formation mediates cytoprotection in diabetic nephropathy by inhibiting glomerular apoptosis. APC prevents glucose-induced apoptosis in endothelial cells and podocytes, the cellular components of the glomerular filtration barrier. APC modulates the mitochondrial apoptosis pathway via the protease-activated receptor PAR-1 and the endothelial protein C receptor EPCR in glucose-stressed cells. These experiments establish a new pathway, in which hyperglycemia impairs endothelial thrombomodulin-dependent APC formation. Loss of thrombomodulin-dependent APC formation interrupts cross-talk between the vascular compartment and podocytes, causing glomerular apoptosis and diabetic nephropathy. Conversely, maintaining high APC levels during long-term diabetes protects against diabetic nephropathy. [ABSTRACT FROM AUTHOR]